Pharmaceutical compositions of tofacitinib for oral administration

ABSTRACT

Liquid pharmaceutical compositions of tofacitinib or its pharmaceutically acceptable salts thereof are described, which are suitable for oral administration, and which are stable under varying storage conditions for extended periods of time. Methods of treating auto-immune disorders are also described, using the stable liquid pharmaceutical compositions of tofacitinib. A stable liquid pharmaceutical composition of tofacitinib according to the invention comprises of (a) tofacitinib at a concentration of about 1 mg/mL or more; (b) a pharmaceutically acceptable liquid vehicle; (c) at least one anti-oxidant; and (d) optionally one or more other pharmaceutically acceptable excipients.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of copending application Ser. No.17/239,007 filed on Apr. 23, 2021, which claims foreign priority toIndian Application No. IN, 202041017604 filed on Apr. 24, 2020, which isincorporated herein by reference in its entirety into the presentspecification.

FIELD OF THE INVENTION

The present invention relates to liquid pharmaceutical compositions oftofacitinib or its pharmaceutically acceptable salts thereof, suitablefor oral administration, that are stable under varying storageconditions for extended periods of time. The present invention alsorelates to methods of treating auto-immune disorders using the stableliquid pharmaceutical compositions of tofacitinib.

BACKGROUND OF THE INVENTION

Tofacitinib citrate is a compound with the chemical name(3R,4R)-4-methyl-3-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-β-oxo-1-piperidinepropanenitrile,2-hydroxy-1,2,3-propanetricarboxylate (1:1), and the following chemicalstructure:

Tofacitinib is an inhibitor of Janus Kinase (JAK) enzyme. Pharmaceuticalcompositions of tofacitinib are approved in the US for the treatment ofrheumatoid arthritis (RA), psoriatic arthritis (PA), ulcerative colitis(UC) and polyarticular course juvenile idiopathic arthritis (pcJIA). Useof tofacitinib compositions for other indications such as treatment ofinflammatory bowel disease, other immunological diseases, as well as forthe prevention of organ transplant rejection is currently beinginvestigated. Tofacitinib citrate is characterized as aBiopharmaceutical Classification System (BCS) class III compound, whichmeans that it has high aqueous solubility and moderate permeability.Solubility of tofacitinib citrate is pH dependent; it ranges from 3.48to 28 mg/mL in aqueous solution of pH 1 to 3.9, and from 0.20 to 0.59mg/mL in aqueous solution of pH 4.53 to 8. The solubility of tofacitinibcitrate at 25° C. in aqueous solutions decreases with an increase in pH.

Tofacitinib compositions in the US are marketed under the brand namesXELJANZ® and XELJANZ® XR. XELJANZ® is available in the form ofimmediate-release film coated tablets (5 mg, 10 mg) and oral solution (1mg/mL). XELJANZ® XR is available as sustained or extended releasetablets (11 mg, 22 mg). Each tablet of XELJANZ® contains 5 mgtofacitinib or 10 mg tofacitinib. Patients with polyarticular coursejuvenile idiopathic arthritis (pcJIA) may be prescribed with XELJANZ®tablet/XELJANZ® oral solution at a recommended dose of 5 mg twice dailyor weight-based equivalent twice daily.

As with any solid oral dosage forms, currently available tabletformulations of tofacitinib have certain disadvantages with respect totheir suitability for pediatric and geriatric patients. First,administration of the solid dosage tablets is considered difficult inpediatric and geriatric populations because of the patients' oftendecreased or low ability of swallow. In order to overcome this issue,caregivers or parents often administer solid formulations usingunscientific, ineffective methods. For example, tablets or powdereddrugs are dissolved in a suitable liquid base to “create” an oralliquid. The tablets are crushed and the resulting powder added to wateror juice; sprinkled onto solid food like apple sauce or pudding.Administration of the solid drugs using these methods is unreliable,tedious and unhygienic.

Second, solid dosage forms are difficult to administer in the absence ofdose dependent formulations for pediatric patients. Formulating andselling a dose dependent pediatric formulation is often not a priorityfor pharmaceutical companies. Consequently, adult formulations are oftenadministered to children on an off-label basis by “breaking” ormodifying the solid forms, which could lead to bioavailability issuesdue to dose errors or inaccurate dosing. This is especially true incases where small amounts of active ingredients are involved, as in thecase of XELJANZ®. Further, tampering of the drug formulation could alsolead to stability issues.

Third, palatability is a major concern for administration of solid oralformulations to pediatric patients.

The above concerns may be remedied by preparing a liquid oralformulation of tofacitinib. Liquid dosage forms such as solutions,syrups or suspensions increase palatability by masking the disagreeabletaste of the active ingredient. They are easy, safe and precise foradministration to patients with compromised swallowing ability. If atall required, liquid formulations allow easy and accurate division tosmaller doses when dose dependent formulations for pediatric patientsare unavailable. Thus, there is a need to develop a stable tofacitinibformulation in the form of a liquid.

However, formulation of tofacitinib into a liquid formulation that isstable for extended periods of time has not been previously possiblebecause of stability issues. Tofacitinib is prone to hydrolytic andoxidative degradation products which may have a significant impact ondrug safety, quality and efficacy. For example, the amide and cyanogroups of the 3-oxopropanenitrile moiety of tofacitinib are susceptibleto hydrolysis in acidic and basic environments. These groups are alsoknown to degrade at higher temperatures. Pyrrole ring double bond oftofacitinib is intrinsically sensitive to oxidation. Further, exposureto light and variations in pH also affects the stability of tofacitinib.Overall, the chemical moieties on tofacitinib make it susceptible todegradation in aqueous environment.

The present invention resolves the above concerns by providing a liquidpharmaceutical composition of tofacitinib for oral administration whichis safe, therapeutically effective, easy to administer, palatable, andstable for extended periods of time, under varying storage conditions.

SUMMARY OF THE INVENTION

The present invention provides a stable liquid pharmaceuticalcomposition of tofacitinib suitable for oral administration comprising:(a) tofacitinib at a concentration of about 1 mg/mL or more; (b) apharmaceutically acceptable liquid vehicle; and (c) optionally, one ormore pharmaceutically acceptable excipients. The composition asdescribed above, wherein pharmaceutically acceptable liquid vehicle isselected from a group consisting of water, purified water, isopropylalcohol, methanol, acetone, ethanol, 1-propanol, butanediol orcombinations thereof.

The composition as described above, wherein pharmaceutically acceptableexcipients are selected from a group consisting of stabilizers,solubilizers, pH adjusting agents, buffering agents, thickening agents,anti-oxidants, chelating agents, preservatives, flavoring agents,sweetening agents, coloring agents and mixtures thereof.

Another aspect of the present invention provides a stable liquidpharmaceutical composition of tofacitinib suitable for oraladministration comprising: (a) tofacitinib at a concentration of about 1mg/mL or more; (b) a pharmaceutically acceptable liquid vehicle; and (c)at least one anti-oxidant.

The composition as described above, wherein pharmaceutically acceptableliquid vehicle is selected from group consisting of water, purifiedwater, isopropyl alcohol, methanol, acetone, ethanol, 1-propanol,butanediol or combinations thereof.

The composition as described above, wherein anti-oxidant is selectedfrom group consisting of acetone, sodium bisulfate, ascorbic acid,ascorbyl palmitate, citric acid, tartaric acid, glycine, L-cysteinehydrochloride, L-methionine, butylated hydroxy anisole (BHA), butylatedhydroxytoluene (BHT), hydro phosphorous acid, monothioglycerol, propylgallate, sodium ascorbate, sodium citrate anhydrous, sodium citratedihydrate, sodium sulfide, sodium sulfite, sodium bisulfate, sodiumformaldehyde sulfoxylate, thioglycolic acid, sodium metabisulfite.

The composition as described above, wherein the anti-oxidant is presentin a concentration ranges from about 0.01% to about 50 w/w of totalcomposition.

The composition as described above, wherein the anti-oxidant is presentin concentration of about 0.05% w/w of total composition.

The composition as described above, wherein the anti-oxidant is tartaricacid.

The composition as described above, wherein the tartaric acid is presentin concentration of about 0.05% w/w of total composition.

The composition as described above, wherein the tartaric acid is presentin an amount of 0.5 mg/mL.

The composition as described above, wherein said composition is stablefor at least 6 months at 25° C./60% RH.

Another aspect of the invention provides a stable liquid pharmaceuticalcomposition of tofacitinib suitable for oral administration comprising:(a) tofacitinib at a concentration of about 1 mg/mL or more; (b) apharmaceutically acceptable liquid vehicle; and (c) at least oneanti-oxidant; and (d) optionally, one or more other pharmaceuticallyacceptable excipients, wherein the pharmaceutical composition is stablefor at least 6 months at 25° C./60% RH.

A stable liquid pharmaceutical composition of tofacitinib suitable fororal administration comprising: (a) tofacitinib at a concentration ofabout 1 mg/mL or more; (b) a pharmaceutically acceptable liquid vehicle;(c) one or more other pharmaceutically acceptable excipients, whereinthe pH of pharmaceutical composition ranges from about 2.5 to about 7.5.

The stable liquid pharmaceutical composition as described above, whereinthe pH of pharmaceutical composition ranges from about 4 to about 4.6.

Another aspect of the invention provides a stable liquid pharmaceuticalcomposition of tofacitinib suitable for oral administration comprising:(a) tofacitinib at a concentration of about 1 mg/mL or more; (b) apharmaceutically acceptable liquid vehicle; and (c) optionally, one ormore other pharmaceutically acceptable excipients, wherein the pH ofpharmaceutical composition ranges from about 4 to about 5, wherein thelevel of Impurity-B in the composition is less than about 0.5% w/w asmeasured by HPLC when stored at 25° C./60% RH or 40° C./75% RH for atleast a period of 6 months.

Another aspect of the invention provides a stable liquid pharmaceuticalcomposition of tofacitinib suitable for oral administration comprising:(a) tofacitinib at a concentration of about 1 mg/mL or more; (b) apharmaceutically acceptable liquid vehicle; (c) at least oneanti-oxidant; and (d) optionally, one or more other pharmaceuticallyacceptable excipients, wherein the pH of pharmaceutical compositionranges from about 4 to about 5, wherein the total level of impurities inthe composition is less than about 3% w/w as measured by HPLC whenstored at 25° C./60% RH or 40° C./75% RH for at least a period of 6months.

Another aspect of the invention provides a stable liquid pharmaceuticalcomposition of tofacitinib suitable for oral administration comprising:(a) tofacitinib at a concentration of about 1 mg/mL or more; (b) apharmaceutically acceptable liquid vehicle; and (c) optionally, one ormore other pharmaceutically acceptable excipients, wherein the pH ofpharmaceutical composition ranges from about 4 to about 5, whereinliquid pharmaceutical composition is free from precipitation when storedat 25° C./60% RH for at least a period of 6 months.

Another aspect of the invention provides a stable liquid pharmaceuticalcomposition of tofacitinib suitable for oral administration comprising:(a) tofacitinib at a concentration of about 1 mg/mL or more; (b)purified water; and (c) tartaric acid; and (d) optionally, one or moreother pharmaceutically acceptable excipients.

Another aspect of the invention provides a stable liquid pharmaceuticalcomposition of tofacitinib suitable for oral administration comprising:(a) tofacitinib at a concentration of about 1 mg/mL or more; (b)purified water and (c) 0.5 mg/mL tartaric acid, wherein the pH ofpharmaceutical composition ranges from about 4 to about 4.6, wherein thelevel of total impurities in the composition is less than about 3% w/was measured by HPLC, when stored at 25° C./60% RH or 40° C./75% RH for aperiod of at least 6 months.

Another aspect of the invention provides a stable liquid pharmaceuticalcompositions of tofacitinib suitable for oral administration comprises(a) tofacitinib at a concentration of about 1 mg/mL or more; (b) apharmaceutically acceptable liquid vehicle and c) optionally one or moreother pharmaceutically acceptable excipients, wherein the pH ofpharmaceutical composition ranges from about 4 to about 4.6, wherein thelevel of Impurity-B in the composition is less than about 0.5% w/w, asmeasured by HPLC when stored at 25° C./60% RH or 40° C./75% RH for aperiod of at least 6 months.

A stable liquid composition suitable for oral administration comprising:(a) tofacitinib at a concentration of about 1 mg/mL or more; (b) apharmaceutically acceptable liquid vehicle; (c) at least oneanti-oxidant; and (d) one or more other pharmaceutically acceptableexcipients, wherein the weight ratio of anti-oxidant to tofacitinib isfrom about 0.1:1 to about 1:10, preferably about 1:3.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all the technical and scientific terms usedherein have the same meanings as commonly known by a person skilled inthe art. In case of conflict, the definitions provided herein willprevail. Unless specified otherwise, all the percentages, portions andratios in the present invention are on weight basis.

The terms “about” and “approximate”, when used along with a numericalvariable, generally means the value of the variable and all the valuesof the variable within an experimental error (e.g. 95% confidenceinterval for the mean) or within a specified value ±10% or within abroader range.

“Tofacitinib” according to the disclosure is tofacitinib free base orits pharmaceutically acceptable salts, solvates or hydrates thereof. Inprinciple, any crystalline form of tofacitinib or amorphous form oftofacitinib may be used for manufacturing the pharmaceutical compositionof the present invention.

The term “pharmaceutically acceptable” substances means those, which,according to a common medical judgment, are suitable to be in contactwith a tissue of a patient without any inappropriate toxicity,irritation, allergic response, etc., have a reasonable balance betweenadvantages and disadvantages, and can be applied to its target useeffectively.

The term “pharmaceutically acceptable salt” refers to tofacitinib saltswhich are formed with inorganic or organic acids. Such salts include,but are not limited to, citrate salt, hydrochloride salt, hydrobromidesalt, oxalate salt, nitrate salt, sulfate salt, phosphate salt, fumaratesalt, succinate salt, maleate salt, besylate salt, tosylate salt,palmitate salt and tartrate salt. Preferably, the pharmaceuticallyacceptable salt is citrate salt.

The terms “pharmaceutical composition,” “liquid pharmaceuticalcomposition,” “pharmaceutical product,” “pharmaceutical dosage form,”“dosage form,” “composition,” “pharmaceutical formulation,” etc., referto a pharmaceutical composition administered to a human subject in needof treatment, which is typically in the form of solution, syrup, elixir,suspension, powder or granules for oral administration.

The terms “dosage”, “dose unit” or “dose” as used herein means theamount of a pharmaceutical formulation comprising therapeutically activeagent(s) administered at a time. “Dosage”, “dose unit” or “dose”includes administration of one or more units of pharmaceuticalformulation administered at the same time.

The term “solution” according to disclosure is a mixture of one or moresubstances dispersed molecularly (i.e., dissolved) in a dissolvingliquid medium or vehicle. The solution is preferably homogeneous, in thesense that each active pharmaceutical ingredient is essentiallyuniformly distributed and concentrated in the solution. The liquidsolution may be viscous (such as syrup) or not.

A “pharmaceutically acceptable vehicle” according to the invention is,without limitation: water, purified water, isopropyl alcohol, methanol,acetone, ethanol, 1-propanol, butanediol or combinations thereof.

An “aqueous solution” according to the disclosure is a solution that isat least 80% water by weight, preferably at least 90% water by weight,more preferably at least 95% water by weight and most preferably atleast 98% water by weight. In certain embodiments, aqueous solutions ofthe present invention include solutions containing appropriatestabilizers, solubilizers, buffering agents, anti-oxidants, chelatingagents, preservatives, sweetening agents, flavoring agents, coloringagents and other pharmaceutically acceptable additives. Alternately,aqueous solutions of the present invention can contain no such additivesand can consist solely of tofacitinib, a stabilizer, and purified water.

The term “solubility” means solubility of tofacitinib or itspharmaceutically acceptable salts in aqueous media such as water,buffer, gastrointestinal simulated fluid, gastrointestinal fluid and thelike.

The terms “stable” and “stability” mean that the evolution of theproduct with time and/or under specific environmental conditions (i.e.,temperature, humidity, etc.) has no significant effects on its quality,safety and/or efficacy for a given time period. It can be measuredthrough the formation of degradation products (impurities), variation ofpH, appearance (precipitation), microbial growth, and/or color. The term“stable” indicates both chemical and physical stability.

The term “degradation product” in the present disclosure refers to anunwanted chemical or impurity (including, but not limited to known orunknown related substances) that can develop during the manufacturing,transportation, and storage of drug products and can affect the efficacyof pharmaceutical products. It can form in response to changes inoxygen, light, temperature, pH, and humidity, or due to inherentcharacteristics of active ingredient, such as their reaction withexcipients or on contact with the packaging.

The term “in vivo” in general means in the living body of a plant oranimal, whereas the term “in vitro” generally means outside the body andin an artificial environment.

A “reference formulation” according to the present disclosure is aformulation that is used for comparison. Preferably, the referenceformulation may refer to immediate release tablet containing 5 mg or 10mg of tofacitinib or extended-release tablet containing 11 mg or 22 mgof tofacitinib or oral solution containing 1 mg/mL of tofacitinib.Preferably, the reference formulation corresponds to an oral dosage formof tofacitinib, which is currently marketed under brand names Xeljanz®(tofacitinib immediate release tablet or oral solution) and Xeljanz® XR(tofacitinib extended release tablet).

The term “peak time of plasma drug concentration (T_(max))” means thetime when peak plasma drug concentration (C_(max)) is attained afterdrug administration.

The term “peak plasma drug concentration (C_(max))” means the maximumplasma drug concentration attained after drug administration.

The term “AUG_(0-infinity)” means the area under a plasma drugconcentration—time curve from time point of 0 to infinity after drugadministration, and the term “AUC_(0-t)” means the area under a plasmadrug concentration—time curve from time point of 0 to t after drugadministration.

Pharmacokinetic parameters for the compositions can be measured in asingle or multiple dose study using a replicate or a non-replicatedesign. For example, the pharmacokinetic parameters can be measured in asingle dose pharmacokinetic study using a two-period, two-sequencecrossover design. Alternately, a four-period, replicate design crossoverstudy may also be used. Pharmacokinetic parameters characterizing rateand extent of tofacitinib absorption are evaluated statistically. Thearea under the plasma concentration-time curve from time zero to thetime of measurement of the last quantifiable concentration (AUC_(0-t))and to infinity (AUC_(0-infinity)), C_(max), and T_(max) can bedetermined according to standard techniques. Statistical analysis ofpharmacokinetic data is performed on logarithmic transformed data (e.g.,AUC_(0-t), AUC_(0-infinity), or C_(max) data) using analysis of variance(ANOVA).

An embodiment of the disclosure is directed to stable liquidpharmaceutical compositions of tofacitinib or its pharmaceuticallyacceptable salt thereof, particularly wherein tofacitinib is present ata concentration of 1 mg/mL or more.

Another embodiment of the disclosure is directed to a pharmaceuticalcomposition of the present application comprises tofacitinib or apharmaceutically acceptable salt thereof, wherein tofacitinibconcentration is about 1 mg/mL to about 10 mg/mL and preferably 1 mg/mL.

Preferably, the liquid pharmaceutical composition will be provided in adosage form that is suitable for oral administration, including but notlimited to a solution, syrup, or elixir. The pharmaceutical compositionsmay be formulated according to conventional pharmaceutical practice.

Generally, the present invention provides stable aqueous tofacitinibsolutions at concentrations higher than the 0.2 mg/mL concentration, andmethods of preparing such solutions. In particular, the presentinvention provides stable aqueous tofacitinib solutions for oraladministration having concentrations about 0.2, 0.3, 0.4, 0.5, 0.6, 0.7,0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1,2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5,3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9,5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9 and 6.0 mg/mL.

An embodiment of the disclosure is directed to a pharmaceuticalcomposition comprising tofacitinib or its pharmaceutically acceptablesalts thereof and an anti-oxidant, wherein the composition furthercomprises additional pharmaceutically acceptable excipients. In anotherembodiment, the pharmaceutical composition of the present inventioncomprises tofacitinib and tartaric acid as anti-oxidant.

In one embodiment of the disclosure, the stable liquid compositionssuitable for oral administration of the present invention comprises (a)tofacitinib at a concentration of 1 mg/mL; (b) purified water; and (c)one or more other pharmaceutically acceptable excipients, wherein theliquid composition is an aqueous solution, a syrup or an elixir.

Another embodiment covers stable liquid compositions suitable for oraladministration comprising (a) tofacitinib at a concentration of 1 mg/mL;(b) purified water; and (c) one or more pharmaceutically acceptableexcipients selected from the group consisting of stabilizers,solubilizers, pH adjusting agents, buffering agents, thickening agents,anti-oxidants, chelating agents, preservatives, flavoring agents,sweetening agents, coloring agents and mixtures thereof.

Another embodiment covers a method for treating and/or preventing anautoimmune disorder/disease in a human subject, comprising administeringstable liquid compositions suitable for oral administration comprising(a) tofacitinib at a concentration of 1 mg/mL; (b) purified water; and(c) one or more pharmaceutically acceptable excipients selected from thegroup consisting of stabilizers, solubilizers, pH adjusting agents,buffering agents, thickening agents, anti-oxidants, chelating agents,preservatives, flavoring agents, sweetening agents, coloring agents andmixtures thereof.

In another embodiment, stable liquid pharmaceutical composition oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) pharmaceuticallyacceptable liquid vehicle; and (c) at least one chelating agent and (d)one or more other pharmaceutically acceptable excipients.

In yet another embodiment, stable liquid pharmaceutical composition oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) pharmaceuticallyacceptable liquid vehicle; and (c) at least one stabilizer; (d) at leastone anti-oxidant and e) one or more other pharmaceutically acceptableexcipients.

In yet another embodiment, stable liquid pharmaceutical composition oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) pharmaceuticallyacceptable liquid vehicle; and (c) at least one anti-oxidant; (d) atleast one chelating agent and e) one or more other pharmaceuticallyacceptable excipients.

In yet another embodiment, stable liquid pharmaceutical composition oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) pharmaceuticallyacceptable liquid vehicle; and (c) at least one stabilizer; (d) at leastone anti-oxidant; (e) at least one chelating agent and f) one or moreother pharmaceutically acceptable excipients.

In yet another embodiment, stable liquid pharmaceutical composition oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) pharmaceuticallyacceptable liquid vehicle; and (c) at least one anti-oxidant; (d) one ormore other pharmaceutically acceptable excipients.

Another embodiment covers stable liquid compositions suitable for oraladministration comprises (a) tofacitinib at a concentration of about 1mg/mL or more; (b) pharmaceutically acceptable liquid vehicle; and (c)at least one anti-oxidant and d) one or more other pharmaceuticallyacceptable excipients, wherein the concentration of the anti-oxidantranges from about 0.1 mg/mL to about 10 mg/mL, from about 0.3 mg/mL toabout 5 mg/mL.

Yet another embodiment covers stable liquid compositions suitable fororal administration comprises (a) tofacitinib at a concentration ofabout 1 mg/mL or more; (b) pharmaceutically acceptable liquid vehicle;and (c) at least one anti-oxidant and (d) one or more otherpharmaceutically acceptable excipients, wherein the weight ratio ofanti-oxidant to tofacitinib is from about 0.1:1 to about 1:10,preferably about 1:3.

In an embodiment, stable liquid pharmaceutical compositions oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) purified water (c)tartaric acid and (d) one or more other pharmaceutically acceptableexcipients, wherein the weight ratio of anti-oxidant to tofacitinib isfrom about 0.1:1 to about 1:10, preferably about 1:3.

In one embodiment, pharmaceutical composition comprising tofacitinib canbe formulated at any suitable pH. The pH of the pharmaceuticalcomposition is preferably from about 4 to about 5, when measured at roomtemperature. In one embodiment, pharmaceutical composition comprisingtofacitinib can be formulated by using any suitable pH adjusting agent.

In an embodiment, stable liquid compositions suitable for oraladministration comprises (a) tofacitinib at a concentration of about 1mg/mL or more; (b) pharmaceutically acceptable liquid vehicle; and (c)at least one anti-oxidant and (d) one or more other pharmaceuticallyacceptable excipients, wherein the composition has a pH in the range ofabout 4 to about 5.

In an embodiment, stable liquid pharmaceutical compositions oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) purified water; (c)tartaric acid and (d) one or more other pharmaceutically acceptableexcipients, wherein pH of pharmaceutical composition ranges from about 4to about 5.

In an embodiment, stable liquid pharmaceutical compositions oftofacitinib suitable for oral administration comprises (a) 1 mg/mLtofacitinib (b) 0.5 mg/mL tartaric acid (c) purified water and (d) oneor more other pharmaceutically acceptable excipients, wherein pH ofpharmaceutical composition ranges from about 4 to about 5.

In an embodiment, stable liquid pharmaceutical compositions oftofacitinib suitable for oral administration comprises (a) 1 mg/mLtofacitinib (b) 0.5 mg/mL tartaric acid (c) purified water and (d) oneor more other pharmaceutically acceptable excipients, wherein the pH ofpharmaceutical composition ranges from about 4 to about 4.6.

In an embodiment, stable liquid pharmaceutical compositions oftofacitinib suitable for oral administration comprises (a) 1 mg/mLtofacitinib (b) 0.5 mg/mL tartaric acid (c) purified water and (d) oneor more other pharmaceutically acceptable excipients, wherein the pH ofpharmaceutical composition ranges from about 4 to about 4.6, wherein thepharmaceutical composition is stable for at least 6 months at 40° C./75%RH.

In an embodiment, stable liquid pharmaceutical compositions oftofacitinib suitable for oral administration comprises (a) 1 mg/mLtofacitinib (b) 0.5 mg/mL tartaric acid (c) purified water and (d) oneor more other pharmaceutically acceptable excipients, wherein the pH ofpharmaceutical composition ranges from about 4 to about 4.6, wherein thelevel of total impurities in the composition is less than about 3% w/was measured by HPLC, when stored at 40° C./75% RH for at least a periodof 6 months.

In an embodiment, stable liquid compositions suitable for oraladministration comprises (a) tofacitinib at a concentration of about 1mg/mL or more; (b) pharmaceutically acceptable liquid vehicle; (c) atleast one anti-oxidant and (d) one or more other pharmaceuticallyacceptable excipients, wherein the composition is stable for at least 6months at 40° C./75% RH.

In an embodiment, stable liquid compositions suitable for oraladministration comprises (a) tofacitinib at a concentration of about 1mg/mL or more; (b) purified water; (c) tartaric acid and (d) one or moreother pharmaceutically acceptable excipients, wherein the composition isstable for at least 6 months at 40° C./75% RH.

In yet another embodiment, stable liquid composition of tofacitinibsuitable for oral administration comprises (a) tofacitinib at aconcentration of about 1 mg/mL or more; (b) one pharmaceuticallyacceptable liquid vehicle; and (c) at least one anti-oxidant and (d) oneor more other pharmaceutically acceptable excipients, wherein thecomposition is stable for at least 6 months at 25° C./60% RH.

In yet another embodiment, stable liquid composition of tofacitinibsuitable for oral administration comprises (a) tofacitinib at aconcentration of about 1 mg/mL or more; (b) purified water; (c) tartaricacid and (d) one or more other pharmaceutically acceptable excipients,wherein the composition is stable for at least 6 months at 25° C./60%RH.

In yet another embodiment, stable liquid composition suitable for oraladministration comprises (a) tofacitinib at a concentration of about 1mg/mL or more; (b) pharmaceutically acceptable liquid vehicle; and (c)at least one anti-oxidant and (d) one or more other pharmaceuticallyacceptable excipients, wherein the composition is stable for at least 12months at 25° C./60% RH.

In yet another embodiment, stable liquid composition suitable for oraladministration comprises (a) tofacitinib at a concentration of about 1mg/mL or more; (b) purified water; (c) tartaric acid and (d) one or moreother pharmaceutically acceptable excipients, wherein the composition isstable for at least 12 months at 25° C./60% RH.

In an embodiment, stable liquid composition suitable for oraladministration comprises (a) tofacitinib at a concentration of about 1mg/mL or more; (b) pharmaceutically acceptable liquid vehicle; and (c)at least one anti-oxidant and (d) one or more other pharmaceuticallyacceptable excipients, wherein the level of total impurities in thecomposition is less than about 3% w/w, preferably less than about 2%w/w, preferably less than about 1.5% w/w, more preferably less thanabout 1% w/w, more preferably less than about 0.5% w/w as measured byHPLC.

In an embodiment, stable liquid composition suitable for oraladministration comprises (a) tofacitinib at a concentration of about 1mg/mL or more; (b) pharmaceutically acceptable liquid vehicle; and (c)at least one anti-oxidant and (d) one or more other pharmaceuticallyacceptable excipients, wherein the level of total impurities in thecomposition is less than about 3% w/w, preferably less than about 2%w/w, preferably less than about 1.5% w/w, more preferably less thanabout 1% w/w, more preferably less than about 0.5% w/w as measured byHPLC, when stored at 25° C./60% RH or 40° C./75% RH for at least aperiod of 6 months.

In an embodiment, stable liquid composition suitable for oraladministration comprises (a) tofacitinib at a concentration of about 1mg/mL or more; (b) pharmaceutically acceptable liquid vehicle; and (c)at least one anti-oxidant and (d) one or more other pharmaceuticallyacceptable excipients, wherein the level of total impurities in thecomposition is less than about 3% w/w, preferably less than about 2%w/w, preferably less than about 1.5% w/w, more preferably less thanabout 1% w/w, more preferably less than about 0.5% w/w as measured byHPLC, when stored at 25° C./60% RH or 40° C./75% RH for at least aperiod of 12 months.

In an embodiment, stable liquid composition suitable for oraladministration comprises (a) tofacitinib at a concentration of about 1mg/mL or more; (b) purified water; and (c) tartaric acid and (d) one ormore other pharmaceutically acceptable excipients, wherein the level oftotal impurities in the composition is less than about 3% w/w,preferably less than about 2% w/w, preferably less than about 1.5% w/w,more preferably less than about 1% w/w, more preferably less than about0.5% w/w as measured by HPLC, when stored at 25° C./60% RH or 40° C./75%RH for at least a period of 6 months.

In an embodiment, one or more pharmaceutically acceptable excipientscombined with tofacitinib comprises stabilizer, solubilizer, sweeteningagent, flavouring agent, preservative, anti-oxidants, chelating agent,viscosity modifier, pH adjusting agent, buffering agent, coloring agentand combinations thereof.

In embodiments, the stabilizer can be selected frompolyvinylpyrrolidone, cyclodextrin or a cyclodextrin derivative. Inembodiments, concentration of stabilizer in the composition ranges fromabout 10% to about 60% w/v of total composition.

In another embodiment, pharmaceutical composition of the presentapplication comprises tofacitinib and a cyclodextrin derivative, whereincyclodextrin derivative concentration is about 10 mg/mL to about 400mg/mL, preferably from about 20 mg/mL to about 80 mg/mL, more preferablyabout 25 mg/mL.

The term “cyclodextrin” refers to cyclic oligosaccharides consisting of(α-1,4)-linked α-D-glucopyranose units. Each subunit of anaturally-occurring (unmodified or parent) cyclodextrin has secondaryhydroxy groups at the 2- and 3-positions and a primary hydroxy group atthe 6-position. A cyclodextrin may be thought of as a toroid or hollowtruncated cone, which because of the location of the hydroxy groups hasa hydrophilic exterior surface and a comparatively less lipophilicinternal cavity. The internal cavity may capture at least a portion of adrug molecule, such as tofacitinib, which results in the formation of aninclusion complex. Covalent bonds are neither made nor broken during theformation of the drug-cyclodextrin complex. In aqueous solution, thecomplex dissociates, resulting in free drug molecules in equilibriumwith drug molecules bound in the cyclodextrin cavities.

In one embodiment, the cyclodextrin of the present application includesα-cyclodextrin, β-cyclodextrin, δ-cyclodextrin, γ-cyclodextrin, orcombinations thereof. In an embodiment, the cyclodextrin of the presentapplication preferably includes either a substituted or non-substitutedβ-cyclodextrin.

Substituted cyclodextrins increase the solubility of the cyclodextrinand mitigate toxic effects associated with unsubstituted cyclodextrins.Examples of substituted cyclodextrins includehydroxypropyl-β-cyclodextrin (HP-β-CD) andsulfobutylether-β-cyclodextrin (SBE-β-CD), Cavasol® W7 HP(hydroxypropyl-β-cyclodextrin (HP-β-CD), Kleptose® HP(hydroxypropyl-β-cyclodextrin (HP-β-CD)), Cavamax® W7 (β-cyclodextrin),Captisol® (sulfoalkyl ether-β-cyclodextrin), Cavasol® W7 M(methyl-β-cyclodextrin), Cavasol® W8 HP (hydroxypropyl-γ-cyclodextrin),Cavamax® W8 (γ-cyclodextrin), Cavamax® W6 (α-cyclodextrin).

In an embodiment, pharmaceutical compositions comprising tofacitinib canbe formulated at any suitable pH using pH adjusting agent and tomaintain pH of the said composition using suitable buffering agent.

In an embodiment, suitable pH adjusting agent include acetic acid,ammonia solution, strong; acetic acid, glacial; ammonium carbonate;anhydrous; diethanolamine; potassium hydroxide; fumaric acid; sodiumbicarbonate; hydrochloric acid; sodium borate; hydrochloric acid,diluted; sodium carbonate; malic acid; trolamine; phosphoric acid;sodium hydroxide; nitric acid; phosphoric acid, diluted; propionic acid;sulfuric acid.

In an embodiment, suitable buffering agents include acetic acid; adipicacid; ammonium carbonate; ammonium phosphate; boric acid; lactic acid;phosphoric acid; potassium citrate; potassium metaphosphate; potassiumphosphate, dibasic; potassium phosphate, monobasic; sodium acetate;sodium citrate; sodium lactate solution; sodium phosphate, dibasic;sodium phosphate, monobasic; succinic acid.

In an embodiment, suitable sweetening agents include aspartame,saccharin, sucralose, acesulfame potassium and the like.

In an embodiment, suitable flavoring agents include cherry flavor,artificial banana flavor, caramel, chocolate mint flavor, grape flavor,wild cherry flavor, maltitol, raspberry flavor, strawberry flavor, mixedberry flavor, citrus flavor, orange flavor, pineapple flavor, citruslime flavor, citrus cream flavor, cherry vanilla flavor, cranberryflavor, creme de menthe flavor and mixtures thereof.

In embodiments, the solubilizer can be selected from but not limited to,for example, propylene glycol, polyethylene glycol, glycerol, Tween 20,Tween 80, sodium lauryl sulfate (SLS) or combinations thereof.

A “chelating agent” according to the disclosure is an agent which formsvia two or more of its functional groups stable complexes with metalcations, e.g., preferably a polyacetic acid or a pharmaceuticallyacceptable salt thereof like disodium EDTA and DTPA. Chelating agentsare capable of forming more than one bond. Ethylene diamine, forexample, is bidentate (two links), tripyridyl is tridentate (three) anddisodium ethylene diamine tetra acetic acid (disodium EDTA) ishexadentate (six) which makes it particularly effective as apharmaceutical chelating agent. One of the consequences of chelationtypically is the formation of a cyclic structure, which may have highthermodynamic and thermal stability.

Preferably the chelating agent is a bivalent cation chelator and morepreferably, the chelator is selected from the group consisting ofdisodium ethylenediaminetetraacetic acid (disodium EDTA),diethylenetriaminepentaacetic acid (DTPA), ethylene glycol-bis(β-aminoethyl ether)-tetra acetic acid (EGTA), N-(hydroxyethyl)ethylenediaminetriacetic acid (HEDTA), nitrilotriacetic acid (NTA),triethanolamine, 8-hydroxyquinoline, phosphoric acid, gluconic acid,saccharic acid, thiodipropionic acid, acetonic dicarboxylic acid,lecithin, di(hydroxyethyl)glycine, phenylalanine, tryptophan, glycerine,sorbitol and pharmaceutically acceptable salts thereof. More preferably,the chelating agent is selected from the group consisting of disodiumEDTA, DTPA, phosphoric acid, gluconic acid or a pharmaceuticallyacceptable salt thereof. The amount of chelating agent may range fromabout 0.1 mg/mL to about 1 mg/mL of the composition.

An “anti-oxidant” according to the disclosure is an agent which inhibitsoxidation and thus is used to prevent the deterioration of preparationsby the oxidative process. Such compounds include by way of example andwithout limitation, acetone, sodium bisulfate, ascorbic acid, ascorbylpalmitate, citric acid, tartaric acid, glycine, L-cysteinehydrochloride, L-methionine, butylated hydroxy anisole (BHA), butylatedhydroxytoluene (BHT), hydro phosphorous acid, monothioglycerol, propylgallate, sodium ascorbate, sodium citrate anhydrous, sodium citratedihydrate, sodium sulfide, sodium sulfite, sodium bisulfate, sodiumformaldehyde sulfoxylate, thioglycolic acid, sodium metabisulfite andothers known to those of ordinary skill in the art. The amount ofanti-oxidant may range from about 0.1 mg/mL to about 50 mg/mL of thecomposition.

In an embodiment of the disclosure, the anti-oxidant concentrationranges from about 0.01% to about 50% w/w of total composition,preferably 0.05% w/w of total composition.

In an embodiment of the disclosure, the anti-oxidant concentrationranges from about 0.01 mg/mL to about 50 mg/mL of total composition,preferably 0.5 mg/mL of total composition.

A suitable viscosity modifier according to the disclosure is celluloseor cellulose derivatives such as ethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, caboxymethylcellulose, sodium hydroxypropylmethylcellulose, hypromellose, methylcellulose, methylethylcellulose,sodium carboxymethylcellulose, Aerosil (silicon dioxide), cetostearylalcohol, cetyl alcohol, stearyl alcohol, Gelucires 33/01, 39/01 and43/01, stearyl alcohol carbomer, xanthan gum, maltodextrin, acacia,tragacanth, povidone and polyvinyl alcohol and mixtures thereof.

In an embodiment of the disclosure, exemplary preservatives includebenzyl alcohol, xylitol, erythorbic acid, fumaric acid, malic acid,propyl gallate, sodium benzoate, parabens (methyl-, ethyl-, butyl-),benzoic acid, potassium sorbate, and vanillin.

Any appropriate form of tofacitinib can be used to prepare oralsolutions of the present invention. For example, any crystalline oramorphous form of tofacitinib may be used in the pharmaceuticalcomposition of the present application. In a preferred embodiment,appropriate forms of tofacitinib include powdered, lyophilized,spray-dried, hot-melt extruded or micro-fluidized tofacitinib. In otherembodiments, the tofacitinib can be provided as an aqueous ornon-aqueous solution of tofacitinib, including buffered solutions.

The pharmaceutical compositions of present application may be filledinto any suitable pharmaceutically acceptable containers. For example,the pharmaceutically acceptable container may be selected from groupconsisting of bottles and syringes. The bottle can be made of anymaterial convenient with the storage and the use requirements comprisingpolymers, metal and glass and so on. It is of importance that the bottlematerial does not interfere with the components of the liquidformulation as disclosed herein. In an embodiment of the disclosure, thepharmaceutically acceptable container is made of glass. In order toprotect the active ingredients from light-induced degradation, apreferred embodiment comprises amber glass bottle.

The bottle capacity can be adapted to the volume to be administrated forthe period during which the liquid formulation as disclosed herein isstable. For instance, a solution which is stable for 60 days afteropening associated to an administration of two doses of 5 mL orweight-based equivalent twice per day may be stored into bottle of about240 mL. The one skilled in the art will easily adapt the volume of thebottle to that needed as previously suggested.

The syringe is made of glass, plastic or any material convenient withthe use and the storage of the liquid solutions as disclosed herein. Thesyringe may be graduated to facilitate the administration of the liquidsolution. In an embodiment, the syringe has 3.2 mL, 4 mL, and 5 mLgradations.

The cap (or closure) is any article for closing a suitably shapedopening. It encompasses, but is not limited to, childproof closures,waterproof closures, pipette-associated caps, solid caps, plastic orpolymeric caps. In an embodiment, the cap is screwed on the bottle topor interlocked with the top of the bottle.

A sealing element may be required for the tightness of the systembottle-cap or bottle-pipette-cap or bottle-pipette or pipette-cap. Thiselement can be supplied on its own and further fit in the bottle-neck,or around the pipette, or in the cap, or it can be previously adapted tothe bottle, the cap or the pipette.

The invention also relates to a kit of parts comprising a packagecontaining bottles of the liquid formulation as disclosed herein andsyringe intended to remove the needed amount of the liquid formulationand/or instructions.

In yet another embodiment, the invention relates to a kit comprising a)a liquid dosage form comprising therapeutically effective amount oftofacitinib; and b) instructions for oral administration of the dosageform.

In another embodiment, the invention relates to a kit of parts allowingthe extemporaneously preparation of the solutions according to theinvention.

In an embodiment, the pharmaceutically acceptable container may be abottle, wherein the bottle was selected from group consisting of a glassbottle and a plastic bottle. Examples of glass bottle include, but arenot limited to Type I, II and III borosilicate glass bottles. In anembodiment, the pharmaceutically acceptable container was a glassbottle, wherein the glass bottle may be amber color glass bottle orclear glass bottle.

Examples of plastic bottles include, but are not limited to,high-density polyethylene (HDPE), polyethylene terephthalate (PET) andpolypropylene (PP) bottles. In an embodiment, the pharmaceuticallyacceptable container is a plastic bottle, wherein the plastic bottle maybe amber color, white opaque or translucent plastic bottle. In preferredembodiment, the HDPE bottles will be available in 30, 60,120, 240, 250,418-mL & 500-mL fill volumes.

In an embodiment, the pharmaceutical composition of present applicationis packed in a kit comprising bottle with child resistant cap, dosingsyringe, adapter and dosing syringe.

Stability. Certain embodiments relate to pharmaceutical compositions asdescribed herein, which are stable, e.g., stable over the shelf life ofthe drug product. In certain aspects, the term “stable” is defined as nomore than about 5% loss of tofacitinib under typical commercial storageconditions. In certain embodiments, the formulations of the presentinvention will have no more than about 3% loss of tofacitinib, morepreferably, no more than about 2% loss of tofacitinib, under typicalcommercial storage conditions. The composition retains at least about95% of the potency of tofacitinib after storing the composition at 40°C. and 75% relative humidity for at least six months. In certainaspects, the term “stable” refers to chemical stability. The formulationaccording to the disclosure is considered stable when not more than 0.5%w/w of each impurity is formed on storage at 40° C. and 75% relativehumidity or at 25° C. and 60% relative humidity for a period of at leastsix months. In certain aspects, the term “stable” refers to chemicalstability, wherein not more than 3% w/w of total impurities formed onstorage at 40° C. and 75% relative humidity or at 25° C. and 60%relative humidity for a period of at least six months.

In an embodiment of the disclosure, stable liquid composition suitablefor oral administration comprises (a) tofacitinib at a concentration ofabout 1 mg/mL or more; (b) pharmaceutically acceptable liquid vehicle;and (c) at least one anti-oxidant and (d) one or more otherpharmaceutically acceptable excipients, wherein the composition isstable for at least 12 months at 25° C./60% RH.

Stability according to the invention is determined by monitoring certainimpurities. In particular, Pyrrolo Pyrimidine impurity, Impurity-A,Impurity-B, Amino Pyrimidine Impurity, N-Oxide Impurity, Ethyl EsterImpurity and 1-Amide impurity are monitored. The structures of theseimpurities are shown below:

Impurity Name IUPAC name Chemical structure Amino Pyrimidine impurity3-{(3R,4R)-3-[(6-aminopyrimidin- 4-yl)(methyl)amino]-4-methylpiperidin-4-yl}-3- oxopropanenitrile impurity

Impurity-B N-methyl-N-[(3R,4R)-4- methylpiperidin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride

Pyrrolo Pyrimidine impurity 3-{(3R,4R)-3-[6,7-dihydro-5Hpyrrolo[2,3-d]pyrimidin-4- yl(methyl)amino]-4-methylpiperidin-1-yl}-3-oxo- propanenitrile

1-Amide impurity or Impurity-L (3R,4R)-4-Methyl-3-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)-β-oxo-1- piperidinepropanamide

N-Oxide impurity (3R,4R)-4-Methyl-3-(methyloxido-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)-β-oxo-1- piperidinepropanenitrile

Impurity-A 3-{(3R,4R)-3-[(2-chloro-7H- pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)amino]-4- methylpiperidin-1-yl}-3- oxopropanenitrile

Ethyl ester impurity Ethyl 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d] pyrimidin-4-yl)amino]piperidin-1-yl}-3-oxoprop

Impurity B is formed when tofacitinib undergoes an acid-base hydrolysis.The acid-base hydrolysis occurs at a pH of below 4 in aqueous solution.It was found that the amount of impurity B observed was above ICHidentification limit of “0.5% known impurity under acceleratedconditions.”

Surprisingly, it was found that when the composition was prepared in apH range from about 4 to about 5, the percentage content of impurity Bwas no more than the 0.5% limit. Thus, the present disclosure provides aliquid pharmaceutical composition of tofacitinib with pH range fromabout 4 to about 5, wherein the level of Impurity-B in the compositionis less than about 0.5% w/w as measured by HPLC, when stored at 25°C./60% RH or 40° C./75% RH for at least a period of 6 months.

In an embodiment, stable liquid pharmaceutical compositions oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) a pharmaceuticallyacceptable liquid vehicle and (c) optionally, one or more otherpharmaceutically acceptable excipients, wherein the pH of pharmaceuticalcomposition ranges from about 4 to about 5, wherein the level ofImpurity-B in the composition is less than about 0.5% w/w as measured byHPLC, when stored at 25° C./60% RH or 40° C./75% RH for at least aperiod of 6 months.

In an embodiment, stable liquid pharmaceutical compositions oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) pharmaceuticallyacceptable liquid vehicle and (c) optionally one or more otherpharmaceutically acceptable excipients, wherein the pH of pharmaceuticalcomposition ranges from about 4 to about 4.6, wherein the level ofImpurity-B in the composition is less than about 0.5% w/w as measured byHPLC, when stored at 25° C./60% RH or 40° C./75% RH for a period of atleast 6 months.

In an embodiment, stable liquid pharmaceutical compositions oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) a pharmaceuticallyacceptable liquid vehicle and (c) at least an anti-oxidant (d)optionally one or more other pharmaceutically acceptable excipients,wherein the pH of pharmaceutical composition ranges from about 4 toabout 4.6, wherein the level of Impurity-B in the composition is lessthan about 0.5% w/w as measured by HPLC, when stored at 25° C./60% RH or40° C./75% RH for a period of at least 6 months.

In an embodiment, stable liquid pharmaceutical compositions oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 ing/mL or more; (b) purified water and (c)optionally one or more other pharmaceutically acceptable excipients,wherein the pH of pharmaceutical composition ranges from about 4 toabout 4.6, wherein the level of impurity-B in the composition is lessthan about 0.5% w/w as measured by HPLC, when stored at 25° C./60% RH or40′C/75% RH for a period of at least 6 months.

In an embodiment, stable liquid pharmaceutical compositions oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) purified water (c)tartaric acid and (d) optionally one or more other pharmaceuticallyacceptable excipients, wherein the pH of pharmaceutical compositionranges from about 4 to about 4.6, wherein the level of Impurity-B in thecomposition is less than about 0.5% w/w as measured by HPLC, when storedat 25° C./60% RH or 40° C./75% RH for a period of at least 6 months.

It was found that variations in pH over 4.6 resulted in precipitation oftofacitinib. For example, at a pH of over 4.6, tofacitinib precipitatesout in aqueous solutions under storage conditions of 25° C./60% RH for aperiod of at least 6 months. Such precipitation is undesirable as itrenders the composition non-compliant with the standard assayspecification. Such a non-compliance is often indicative of thecomposition's lack of prolonged shelf life.

Surprisingly, it was found that a composition with pH below 4.8 did notresult stability issues arising from tofacitinib precipitation. Thepresent disclosure provides a liquid pharmaceutical composition oftofacitinib with pH range from about 3.7 to about 4.6, was found to befree from precipitation, when stored at 25° C./60% RH for at least aperiod of 6 months.

The present disclosure provides a stable liquid pharmaceuticalcompositions of tofacitinib suitable for oral administration comprises(a) tofacitinib at a concentration of about 1 mg/mL or more; (b) apharmaceutically acceptable liquid vehicle; and (c) optionally, one ormore other pharmaceutically acceptable excipients, wherein the pH ofpharmaceutical composition is not more than 4.6, wherein liquidpharmaceutical composition is free from precipitation, when stored at25° C./60% RH for at least a period of 6 months.

In an embodiment, stable liquid pharmaceutical compositions oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) a pharmaceuticallyacceptable liquid vehicle; and (c) optionally, one or more otherpharmaceutically acceptable excipients, wherein the pH of pharmaceuticalcomposition range from about 3.7 to about 4.6, wherein liquidpharmaceutical composition is free from precipitation, when stored at25° C./60% RH for at least a period of 6 months.

In an embodiment, stable liquid pharmaceutical compositions oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) a pharmaceuticallyacceptable liquid vehicle (c) at least one anti-oxidant and (d)optionally, one or more other pharmaceutically acceptable excipients,wherein the pH of pharmaceutical composition range from about 3.7 toabout 4.6, wherein liquid pharmaceutical composition is free fromprecipitation, when stored at 25° C./60% RH for at least a period of 6months.

In an embodiment, stable liquid pharmaceutical compositions oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) purified water (c)tartaric acid and (d) optionally one or more other pharmaceuticallyacceptable excipients, wherein the pH of pharmaceutical compositionranges from about 3.7 to about 4.6, wherein liquid pharmaceuticalcomposition is free from precipitation, when stored at 25° C./60% RH forat least a period of 6 months.

In yet another embodiment, stable liquid pharmaceutical composition oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) pharmaceuticallyacceptable liquid vehicle; and (c) at least one anti-oxidant and (d) oneor more other pharmaceutically acceptable excipients, wherein thepharmaceutical composition is stable for at least 6 months at 40° C./75%RH.

In yet another embodiment, stable liquid pharmaceutical composition oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) purified water; (c)tartaric acid and (d) one or more other pharmaceutically acceptableexcipients, wherein the pharmaceutical composition is stable for atleast 6 months at 40° C./75% RH.

In yet another embodiment, stable liquid pharmaceutical composition oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) pharmaceuticallyacceptable liquid vehicle; and (c) at least one anti-oxidant and (d) oneor more other pharmaceutically acceptable excipients, wherein thepharmaceutical composition is stable for at least 6 months at 25° C./60%RH.

In yet another embodiment, stable liquid pharmaceutical composition oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) purified water (c)tartaric acid and (d) one or more other pharmaceutically acceptableexcipients, wherein the pharmaceutical composition is stable for atleast 6 months at 25° C./60% RH.

In yet another embodiment, stable liquid pharmaceutical composition oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) pharmaceuticallyacceptable liquid vehicle; and (c) at least one anti-oxidant and (d) oneor more other pharmaceutically acceptable excipients, wherein thepharmaceutical composition is stable for at least 12 months at 40°C./75% RH.

In yet another embodiment, stable liquid pharmaceutical composition oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) purified water; (c)tartaric acid and (d) one or more other pharmaceutically acceptableexcipients, wherein the pharmaceutical composition is stable for atleast 12 months at 40° C./75% RH.

In yet another embodiment, stable liquid pharmaceutical composition oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) pharmaceuticallyacceptable liquid vehicle; and (c) at least one anti-oxidant and (d) oneor more other pharmaceutically acceptable excipients, wherein thepharmaceutical composition is stable for at least 12 months at 25°C./60% RH.

In yet another embodiment, stable liquid pharmaceutical composition oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) purified water; (c)tartaric acid and (d) one or more other pharmaceutically acceptableexcipients, wherein the pharmaceutical composition is stable for atleast 12 months at 25° C./60% RH.

In an embodiment, stable liquid pharmaceutical composition oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) at least onepharmaceutically acceptable liquid vehicle; and (c) at least oneanti-oxidant and (d) one or more other pharmaceutically acceptableexcipients, wherein the level of total impurities in the composition isless than about 3% w/w, preferably less than about 2% w/w, preferablyless than about 1.5% w/w, more preferably less than about 1% w/w, morepreferably less than about 0.5% w/w as measured by HPLC.

In an embodiment, stable liquid pharmaceutical composition oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) purified water; and (c)tartaric acid and (d) one or more other pharmaceutically acceptableexcipients, wherein the level of total impurities in the composition isless than about 3% w/w, preferably less than about 2% w/w, preferablyless than about 1.5% w/w, more preferably less than about 1% w/w, morepreferably less than about 0.5% w/w as measured by HPLC.

In an embodiment, a stable liquid pharmaceutical composition oftofacitinib suitable for oral administration comprising: (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) a pharmaceuticallyacceptable liquid vehicle; (c) one or more other pharmaceuticallyacceptable excipients, wherein the pH of pharmaceutical compositionranges from about 2.5 to about 7.5.

In an embodiment, stable liquid pharmaceutical compositions oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) pharmaceuticallyacceptable liquid vehicle; and (c) at least one anti-oxidant and (d) oneor more other pharmaceutically acceptable excipients, wherein pH ofpharmaceutical composition ranges from about 2.5 to about 7.5,preferably from about 3.5 to about 5.5, preferably from about 4 to about5, wherein the level of total impurities in the composition is less thanabout 3% w/w, preferably less than about 2% w/w, preferably less thanabout 1.5% w/w, more preferably less than about 1% w/w, more preferablyless than about 0.5% w/w as measured by HPLC.

In an embodiment, stable liquid pharmaceutical compositions oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) purified water (c)tartaric acid and (d) one or more other pharmaceutically acceptableexcipients, wherein pH of pharmaceutical composition ranges from about2.5 to about 7.5, preferably from about 3.5 to about 5.5, preferablyfrom about 4 to about 5, wherein the level of total impurities in thecomposition is less than about 3% w/w, preferably less than about 2%w/w, preferably less than about 1.5% w/w, more preferably less thanabout 1% w/w, more preferably less than about 0.5% w/w as measured byHPLC.

In an embodiment, stable liquid pharmaceutical compositions oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) purified water (c)tartaric acid and (d) one or more other pharmaceutically acceptableexcipients, wherein pH of pharmaceutical composition ranges from about 4to about 5, wherein the level of total impurities in the composition isless than about 3% w/w as measured by HPLC.

In an embodiment, stable liquid pharmaceutical compositions oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) purified water (c) 0.5mg/mL tartaric acid and (d) one or more other pharmaceuticallyacceptable excipients, wherein pH of pharmaceutical composition rangesfrom about 4 to about 4.6, wherein the level of total impurities in thecomposition is less than about 3% w/w as measured by HPLC.

In an embodiment, stable liquid pharmaceutical compositions oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) purified water (c)0.05% w/w anti-oxidant and (d) one or more other pharmaceuticallyacceptable excipients, wherein pH of pharmaceutical composition rangesfrom about 4 to about 4.6, wherein the level of total impurities in thecomposition is less than about 3% w/w as measured by HPLC.

In an embodiment, stable liquid pharmaceutical compositions oftofacitinib suitable for oral administration comprises (a) tofacitinibat a concentration of about 1 mg/mL or more; (b) purified water (c)0.05% w/w tartaric acid and (d) one or more other pharmaceuticallyacceptable excipients, wherein pH of pharmaceutical composition rangesfrom about 4 to about 4.6, wherein the level of total impurities in thecomposition is less than about 3% w/w as measured by HPLC.

Dosage and Administration. The dose of the therapeutic compound will bein the range from about 0.1 to about 50 mg/mL per recipient per day.Exemplary doses of therapeutic compound range from 0.1 mg/mL to 50mg/mL, including dosages of 0.1 mg/mL, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL,0.5 mg/mL, 0.6 mg/mL, 0.7 mg/mL, 0.8 mg/mL, 0.9 mg/mL, 1 mg/mL, 2 mg/mL,3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL,11 mg/mL, 12 mg/mL, 13 mg/mL, 14 mg/mL, 15 mg/mL, 16 mg/mL, 17 mg/mL, 18mg/mL, 19 mg/mL, 20 mg/mL, 21 mg/mL, 22 mg/mL, 25 mg/mL, 30 mg/mL, 35mg/mL, 40 mg/mL, 45 mg/mL, 50 mg/mL. The effective dosage range of thepharmaceutically acceptable salts may be calculated based on the weightof the active moiety to be delivered. If the salt exhibits activityitself, the effective dosage may be estimated as above using the weightof the salt, or by other means known to those skilled in the art.

As used herein, “to treat” a condition or “treatment” of the conditionis an approach for obtaining beneficial or desired results, such asclinical results. Beneficial or desired results can include, but are notlimited to, alleviation or amelioration of one or more symptoms orconditions; diminishment of extent of disease, disorder, or condition;stabilized (i.e., not worsening) state of disease, disorder, orcondition; preventing spread of disease, disorder, or condition; delayor slowing the progress of the disease, disorder, or condition;amelioration or palliation of the disease, disorder, or condition; andremission (whether partial or total), whether detectable orundetectable. “Palliating” a disease, disorder, or condition means thatthe extent and/or undesirable clinical manifestations of the disease,disorder, or condition are lessened and/or time course of theprogression is slowed or lengthened, as compared to the extent or timecourse in the absence of treatment.

For administration to animal or human subjects, the pharmaceuticalcompositions comprise an effective dosage amount of tofacitinib or apharmaceutically acceptable salt thereof. The formulation may beprepared using conventional methods, for example, depending on thesubject to be treated, the mode of administration, and the type oftreatment desired (e.g., prevention, prophylaxis, or therapy).

The dosage levels can be dependent on the nature of the condition, drugefficacy, the condition of the patient, the judgment of thepractitioner, and the frequency and mode of administration. The dosescan be administered to achieve any daily amount described herein, suchas by administering one to five times daily (e.g., one, two, three,four, or five times daily).

“Effective amount” according to the disclosure is the amount of a drugsufficient to treat, prevent, or ameliorate a condition in a subject orpatient. The effective amount of tofacitinib or pharmaceuticallyacceptable salt thereof, used to practice the present invention fortherapeutic management of a condition may be determined and adjusted bya person of ordinary skill to provide the appropriate amount and dosageregimen, e.g., depending upon one or more of the manner ofadministration, the age, body weight, sex, and/or general health of thepatient.

In an embodiment, the pharmaceutical compositions of the presentinvention were subjected to freeze-thaw cycle testing to determinestability, phase separation or precipitation or crystallization underhigh and low temperature conditions. Freeze-thaw testing is conducted byexposing the compositions filled in centrifuge tube to freezingtemperatures (−20° C.) for at least 8 hours, and then samples were keptat 25° C. for at least 8 hours. This process is referred to as oneFreeze-thaw cycle. Samples were subjected to at least 1 to 5 Freeze-thawcycles and the samples were analyzed visually for particles or crystals.

Preparation of 0.1 N NaOH. 0.4 gm of sodium hydroxide (NaOH) pellet wasadded to 50 mL of purified water in volumetric flask and stirred tocompletely dissolve NaOH. 20 mL of purified water was added to theobtained solution and stirred. Volume was made up to 100 mL withpurified water and mix solution thoroughly. Keep the solution for atleast 1 hour at room temperature.

HPLC procedure for analysis of samples. The samples withdrawn from thedifferent compositions at different storage conditions were analyzed forimpurity profile using the following HPLC procedure. The materials andgeneral conditions are listed below:

TABLE 1 Chromatographic conditions Column Sunfire C18, 250 × 4.6 mm, 5μ(Part No: 186002560) Column temperature 35° C. Sample temperature 25° C.Injection volume 20 L Flow rate 1.0 mL/min Detection 286 & 230 nm forAmino Pyrimidine Run Time 85 min Mode of elution Gradient Needle WashWater: Acetonitrile: 20:80% v/v

TABLE 2 Gradient program Time (min) % A % B 0.01 95 5 25 85 15 30 80 2040 75 25 55 65 35 60 60 40 65 50 50 70 40 60 75 20 80 78 95 5 85 95 5

HPLC procedure for analysis of samples. The samples withdrawn from thedifferent compositions at different storage conditions were analyzed forassay for tofacitinib using the following HPLC procedure. The materialsand general conditions are listed below:

TABLE 3 Chromatographic conditions Column Kinetex XB C18, 100 A°, 150 ×4.6 mm, 2.6μ (Part no: 00F-44496-E0) Column Temperature 30° C. SampleTemperature 25° C. Detector Wavelength 220 nm with PDA/UV detector PumpMode Gradient Flow Rate 0.8 mL/minutes Injection Volume 10 μL Retentiontime 18 minutes Needle Wash Water:Acetonitrile 20:80% v/v Time (min) % A% B Gradient Table 0.01 60 40 8 60 40 10 10 90 12 10 90 13 60 40 18 6040

EXAMPLES

The following examples are exemplary and not intended to be limiting.The above disclosure provides many different embodiments forimplementing the features of the invention, and the following examplesdescribe certain embodiments. It will be appreciated that othermodifications and methods known to one of ordinary skill in the art canalso be applied to the following experimental procedures, withoutdeparting from the scope of the invention.

Example 1. The Composition of Tofacitinib Solutions are Set Forth Belowin Table 4

TABLE 4 Composition- Composition- Composition- 1 2 3 IngredientsQuantity in mg/batch (Batch size - 100 mL) Tofacitinib citrate* 161.6 mg161.6 mg 161.6 mg HP-β-CD  1000 mg  1000 mg  1000 mg Tartaric acid   100mg — — Sodium sulfite —   100 mg — Sodium — —   200 mg metabisulfitePurified water q.s. to 100 mL q.s. to 100 mL q.s. to 100 mL q.s.:quantity sufficient *Note: 161.6 mg of tofacitinib citrate equivalent to100 mg of tofacitinib

Manufacturing procedure of Composition-1, 2 and 3: About 90 mL of thepurified water was taken in manufacturing vessels. 1 g of HP-β-CD wasadded to each manufacturing vessel and stirred for 5-10 minutes toobtain clear solutions. 161.6 mg of tofacitinib citrate was added toeach manufacturing vessel and stirred continuously for 15 minutes toobtain clear solutions. As mentioned in Table 4, specified quantities oftartaric acid, sodium sulfite and sodium metabisulfite were added toComposition-1, 2 and 3 respectively and stirred for 5-10 minutes toobtain clear solutions. Sufficient quantities of purified water wereadded to make up volumes to 100 mL. Room temperature condition wasmaintained throughout the preparation of solutions.

Samples of Composition 1, 2 and 3 were stored and analyzed at stressconditions (i.e., 40° C./75% RH condition and 60° C. condition). Samplesof Composition-1, 2 and 3 were stored for 7 days at 40° C./75% relativehumidity (RH) condition as well as for 5 days at 60° C. conditions,Tofacitinib Citrate remains solubilized and compositions were found tobe clear without any recrystallization or precipitation. Initial samplesof Composition-1, 2 and 3 were also subjected to freeze thaw cycling andobserved for any visible particles or crystals by visual observation. Novisible particles or crystal particles were observed in Composition-1, 2and 3 after five freeze thaw cycles. Samples of Composition-1, 2 and 3were analyzed for impurity profile, which were stored for 7 days at 40°C./75% RH condition and for 5 days at 60° C. conditions and data givenin the below Table 5.

TABLE 5 Composition-1 Composition-2 Composition-3 40° C./ 40° C./ 40°C./ Condition 60° C. 75% RH 60° C. 75% RH 60° C. 75% RH Duration 5 Days7 Days 5 Days 7 Days 5 Days 7 Days Pack Centrifuge tube (Polyvinylchloride (PVC)) Visual Clear Clear Clear Clear Clear Clear observationof solution Impurities (% w/w) Pyrrolo 0.07 0.08 0.05 0.06 0.04 0.05Pyrimidine Impurity Impurity-A 0.01 0.01 0.01 0.01 0.01 0.01 Impurity-B0.65 0.17 0.06 ND 0.16 0.12 N-Oxide 0.01 0.01 0.16 ND 0.04 ND ImpurityAmino 0.01 0.01 0.05 0.02 0.03 0.02 Pyrimidine Impurity Ethyl Ester 0.01ND 0.01 0.01 0.02 ND Impurity Total 0.02 0.02 3.83 6.21 3.74 1.10Unknown (1.95) (1.62) (0.48) (0.48) (1.02) (0.48) Impurity (at RRT)Total 0.85 0.36 11.77 18.24 12.21 3.60 impurities

Example 2. The Compositions of Tofacitinib Solutions are Set Forth Belowin Table 6

TABLE 6 Composition 4 5 6 7 8 9 Batch size 1 L 3 L 1 L 1 L 1 L I LIngredients Quantity (mg/mL) Tofacitinib Citrate 1.620* 1.620* 1.620*1.620* 1.620* 1.620* Sodium Benzoate 2.000 2.000 2.000 2.000 2.000 2.000Grape flavor 2.000 2.000 2.000 2.000 2.000 2.000 Sucralose 3.000 3.0003.000 3.000 3.000 3.000 Tartaric Acid 0.500 0.500 0.500 0.500 0.500 —Sodium Acetate 1.000 1.000 1.000 1.000 1.000 up to 1 mL Purified Waterq.s. up q.s. up q.s. up q.s. up q.s. up — to 1 mL to 1 mL to 1 mL to 1mL to 1 mL pH of final 4.0 4.25 4.5 4.8 5.0 3.7 composition *1.620 mg oftofacitinib citrate is equivalent to 1 mg of tofacitinib

Manufacturing procedure of Composition-4, 6, 7 and 8: 950 mL of purifiedwater was dispensed into suitable container. 0.5 gm of tartaric acid wasadded to purified water and continuous stirred at 25° C.±5° C. to obtaina solution-1. 1.62 gm of tofacitinib citrate was added to solution-1 andcontinuous stirred at 25° C.±5° C. to obtain a solution-2. 1 gm ofsodium acetate was added to solution-2 and continuous stirred at 25°C.±5° C. to obtain a solution-3. 2 gm of sodium benzoate was added tosolution-3 and continuous stirred at 25° C.±5° C. to obtain asolution-4. 3 gm of sucralose was added to solution-4 and continuousstirred at 25° C.±5° C. to obtain a solution-5. 2 gm of Grape flavor wasadded to solution-5 and continuous stirred at 25° C.±5° C. to obtain asolution-6. Required quantity of purified water was added to solution-6to make up volume up to 980 mL and mixed for 10 minutes to solution-7.pH of solution-7 was adjusted by adding required quantity of 1N HCl.Purified water was added to the pH adjusted solution to make up volumeup to 1000 mL and mixed for next 10 minutes to obtain final solution.The above described manufacturing procedure is same for Composition-32,34, 35, 36 except the 1N HCl quantity required to obtain different pHvalues (i.e., 4.0, 4.5, 4.8 & 5.0 respectively) for the compositions.

Manufacturing procedure of Composition-5: 2850 mL of purified water wasdispensed into suitable container. 1.5 gm of tartaric acid was added topurified water and continuous stirred at 25° C.±5° C. to obtain asolution-1. 4.848 gm of tofacitinib citrate was added to solution-1 andcontinuous stirred at 25° C.±5° C. to obtain a solution-2. 3 gm ofsodium acetate was added to solution-2 and continuous stirred at 25°C.±5° C. to obtain a solution-3. 6 gm of sodium benzoate was added tosolution-3 and continuous stirred at 25° C.±5° C. to obtain asolution-4. 9 gm of sucralose was added to solution-4 and continuousstirred at 25° C.±5° C. to obtain a solution-5. 6 gm of Grape flavor wasadded to solution-5 and continuous stirred at 25° C.±5° C. to obtain asolution-6. Required quantity of purified water was added to solution-6to make up volume up to 2940 mL and mixed for 10 minutes to solution-7.pH of solution-7 was adjusted to 4.25 by adding required quantity of 1NHCl. Purified water was added to the pH adjusted solution to make upvolume up to 3000 mL and mixed for next 10 minutes to obtain finalsolution with pH value 4.25.

Manufacturing procedure of Composition-9: 950 mL of pH 4.5 acetatebuffer was dispensed into suitable container. 1.62 gm of tofacitinibcitrate was added to acetate buffer and continuous stirred at 40° C.±2°C. to obtain a solution-1. 2 gm of sodium benzoate was added tosolution-1 and continuous stirred at 25° C.±5° C. to obtain asolution-2. 3 gm of sucralose was added to solution-2 and continuousstirred at 25° C.±5° C. to obtain a solution-3. 2 gm of Grape flavor wasadded to solution-3 and continuous stirred at 25° C.±5° C. to obtain asolution-4. Required quantity of purified water was added to solution-4to make up volume up to 980 mL and mixed for 10 minutes to solution-5.pH of solution-5 was adjusted to 3.7 by adding required quantity of 1NHCl. Purified water was added to the pH adjusted solution to make upvolume up to 1000 mL and mixed for next 10 minutes to obtain finalsolution with pH value 3.7.

Example 3

TABLE 7 Stability data of Composition-4 Composition-4 Condition RT* 40°C./75% RH 25° C./60% RH Duration (in months) Initial 3 6 3 6 DescriptionClear, Colourless solution pH of final solution 4.00 3.96 3.91 3.96 3.91Tofacitinib assay 99.7 104.5 99.3 103.2 100.4 Impurity profile &Specification (% w/w) limit (NMT % w/w) Impurity-B 0.5% 0.011 0.2040.385 0.054 0.083 Amino-pyrimidine Impurity 0.5% ND ND ND ND ND PyrroloPyrimidine 0.5% 0.103 0.093 0.092 0.096 0.096 Impurity N-oxide Impurity0.5% ND ND ND ND ND 1-Amide Impurity 0.5% 0.002 0.006 0.009 0.003 NDIndividual maximum 0.2% 0.022 0.022 0,021 0.023 0.013 unspecifiedimpurity (1.58) (1.54) (0.98) (1.54) (1.54) (RRT) Total Impurities 3.0%0.191 0.368 0.531 0.214 0.192 *RT = Room Temperature; RRT = RelativeRetention Time; NMT = Not More Than

TABLE 8 Stability data of Composition-5 Composition-5 Condition RT* 40°C./75% RH 25° C./60% RH Duration (in months) Initial 3 6 3 6 DescriptionClear, Colourless solution pH of final solution 4.26 4.25 4.22 4.23 4.22Tofacitinib Assay 101.5 100.6 102.7 98.9 103.2 Impurity profile &Specification (% w/w) limit (NMT % w/w) Impurity-B 0.5% 0.021 0.1460.309 0.034 0.066 Amino-pyrimidine Impurity 0.5% ND ND ND ND ND PyrroloPyrimidine Impurity 0.5% 0.106 0.099 0.085 0.101 0.095 N-oxide Impurity0.5% ND ND ND ND ND 1-Amide Impurity 0.5% ND 0.005 0.008 ND NDIndividual maximum 0.2% 0.019 0.020 0.028 0.018 0.008 unspecifiedimpurity (1.58) (0.67) (0.98) (1.54) (1.77) (RRT) Total Impurities 3.0%0.190 0.345 0.458 0.185 0.169

TABLE 9 Stability data of Composition-6 Composition-6 Condition RT* 40°C./75% RH 25° C./60% RH Duration (in months) Initial 3 6 3 6 DescriptionClear, Colourless solution pH of final solution 4.52 4.48 4.43 4.49 4.42Tofacitinib Assay 100 101.8 99.2 102.6 99.7 Impurity profile &Specification (% w/w) limit (NMT % w/w) Impurity-B 0.5% 0.018 0.1690.313 0.043 0.063 Amino-pyrimidine Impurity 0.5% ND ND ND ND ND PyrroloPyrimidine Impurity 0.5% 0.156 0.100 0.100 0.100 0.102 N-oxide Impurity0.5% ND ND ND ND ND 1-Amide Impurity 0.5% 0.003 0.006 0.009 0.003 NDIndividual maximum 0.2% 0.03 0.028 0.042 0.023 0.014 unspecifiedimpurity (1.83) (0.99) (0.98) (1.54) (1.54) (RRT) Total Impurities 3.0%0.301 0.392 0.539 0.238 0.205

TABLE 10 Stability data of Composition-7 Composition-7 Condition RT* 40°C./75% RH 25° C./60% RH Duration (in months) Initial 3 6 3 6 DescriptionClear, Particles Particles Particles Colourless observed observedobserved solution pH of final solution 4.80 4.73 4.79 4.69 4.69Tofacitinib Assay 96.7 97.4 96.9 29.9 29.6 Impurity profile & (% w/w)Specification limit (NMT % w/w) Impurity-B 0.5% 0.03 0.169 Analysis 0.03Analysis Amino-pyrimidine 0.5% ND ND not done ND not done Impurity asparticles as particles Pyrrolo Pyrimidine 0.5% 0.085 0.095 observed.0.09 observed. Impurity N-oxide Impurity 0.5% ND ND ND 1-Amide Impurity0.5% ND 0.004 0.001 Individual maximum 0.2% ND 0.018 0.01 unspecifiedimpurity (0.18) (0.63) (RRT) Total Impurities 3.0% 0.11 0.353 0.131

TABLE 11 Stability data of Composition-8 Composition-8 Condition RT* 40°C./75% RH 25° C./60% RH Duration (in months) Initial 3 6 3 6 DescriptionClear, Colourless Particles Particles Particles solution observedobserved observed pH of final solution 5.00 4.88 4.81 4.81 4.85Tofacitinib Assay 100.5 NA NA 38.7 22.3 Impurity profile & Specificationlimit (NMT % w/w) (% w/w) Impurity-B 0.5% 0.012 0.211 Analysis not doneas particles Amino-pyrimidine 0.5% ND ND observed. Impurity PyrroloPyrimidine 0.5% 0.104 0.090 Impurity N-oxide Impurity 0.5% ND ND 1-AmideImpurity 0.5% 0.002 0.008 Individual maximum 0.2% 0.010 0.025unspecified impurity (0.94) (0.98) (RRT) Total Impurities 3.0% 0.1520.410

TABLE 12 Stability data of Composition-9 Composition-9 Condition RT* 40°C./75% RH 25° C./60% RH Duration (in months) Initial 6 6 DescriptionClear, Colourless solution pH of final solution 3.70 3.79 3.80Tofacitinib Assay 98.5 99.2 100.1 Impurity profile & Specification limit(NMT % w/w) (% w/w) Impurity-B 0.5% 0.015 0.801 0.193 Amino-pyrimidineImpurity 0.5% ND ND ND Pyrrolo Pyrimidine Impurity 0.5% 0.099 0.0640.086 N-oxide Impurity 0.5% ND ND ND 1-Amide Impurity 0.5% ND 0.0330.009 Individual maximum 0.2% 0.009 0.023 0.013 unspecified impurity(RRT) (1.3) (0.98) (1.54) Total Impurities 3.0% 0.155 0.97  0.317

Example 4. Tofacitinib Solutions Having Compositions were Set Forth inTable 13

TABLE 13 Composition-10 Composition-11 Ingredients Quantity (mg/mL);Batch size = 1 L Tofacitinib citrate 1.620* 1.620* Tartaric acid — 1.00HP-β-CD 25.00 25.00 Sodium benzoate 2.000 2.000 Mixed berry flavor 2.0002.000 Sucralose 3.000 3.000 Purified water up to 1 mL up to 1 mL *1.620mg of tofacitinib citrate is equivalent to 1 mg of tofacitinib

Manufacturing procedure of Composition-10. 950 mL of purified water wasdispensed into suitable container and heated to 50° C.±2° C. 25 gm ofHP-β-CD was added to purified water and continuous stirred at 50° C.±2°C. to obtain a solution-1. 1.62 gm of tofacitinib citrate was added tosolution-1 and continuous stirred at 40° C.±2° C. to obtain asolution-2. 2 gm of sodium benzoate was added to solution-2 andcontinuous stirred at 35° C.±5° C. to obtain a solution-3. 3 gm ofsucralose was added to solution-3 and continuous stirred at 25° C.±5° C.to obtain a solution-4. 2 gm of mixed berry flavor was added tosolution-4 and continuous stirred at 25° C.±5° C. to obtain asolution-5. Required quantity of purified water was added to solution-5to make up volume up to 1000 mL and mixed for 10 minutes to finalsolution.

Manufacturing procedure of Composition-11. 950 mL of purified water wasdispensed into suitable container and heated to 50° C.±2° C. 25 gm ofHP-β-CD was added to purified water and continuous stirred at 50° C.±2°C. to obtain a solution-1. 1.62 gm of tofacitinib citrate was added tosolution-1 and continuous stirred at 40° C.±2° C. to obtain asolution-2. 2 gm of sodium benzoate was added to solution-2 andcontinuous stirred at 35° C.±5° C. to obtain a solution-3. 3 gm ofsucralose was added to solution-3 and continuous stirred at 25° C.±5° C.to obtain a solution-4. 2 gm of mixed berry flavor was added tosolution-4 and continuous stirred at 25° C.±5° C. to obtain asolution-5. 1 gm of tartaric was added to solution-5 and continuousstirred at 25° C.±5° C. to obtain a solution-6. Required quantity ofpurified water was added to solution-5 to make up volume up to 1000 mLand mixed for 10 minutes to final solution.

Oxidative stress testing: Composition-10 & 11 were exposed to oxidationstress conditions to observe oxidative impurity formation. Table 14contains information of the two different oxidation stress conditionsused to generate oxidative stress and total impurities profile ofComposition-10 & 11 were compared under these conditions.

TABLE 14 Total Impurities data of Tofacitinib oral solution 1 mg/mLunder oxidative stress % Total Impurities Oxidative Stress ConditionComposition-10 Composition-11 Exposure of sample to 5% Hydrogen  1.95%0.57% peroxide solution at 60° C. for 60 minutes Exposure of sample to30% Hydrogen 18.47% 4.46% peroxide solution at 60° C. for 60 minutesWhile the invention has been described above with reference to specificembodiments thereof, it is apparent that many changes, modifications,and variations can be made without departing from the inventive conceptdisclosed herein, and such description is not intended as limitations onthe scope thereof. Accordingly, it is intended to embrace all suchchanges, modifications, and variations that fall within the spirit andbroad scope of the appended claims.

1. A stable solution of tofacitinib consisting essentially of:tofacitinib at a concentration of about 1 mg/mL; optionally one or moreantioxidants; and a pharmaceutically acceptable liquid vehicle selectedfrom the group consisting of water, purified water, ethanol or acombination thereof; wherein a pH of the solution ranges from about 3.7to 4.5; wherein the solution is free from precipitation when saidsolution is stored at 25° C./60% RH for at least 6 months; and whereinsaid solution is a palatable oral solution.
 2. The solution according toclaim 1, wherein said solution further comprises one or more additionalpharmaceutically acceptable excipients selected from the groupconsisting of stabilizers, solubilizers, pH adjusting agents, bufferingagents, thickening agents, chelating agents, preservatives, flavoringagents, sweetening agents, coloring agents and mixtures thereof.
 3. Thesolution according to claim 1, wherein the antioxidant is selected fromthe group consisting of sodium bisulfate, ascorbic acid, ascorbylpalmitate, citric acid, tartaric acid, glycine, L-cysteinehydrochloride, L-methionine, butylated hydroxy anisole (BHA), butylatedhydroxytoluene (BHT), hydro phosphorous acid, monothioglycerol, propylgallate, sodium ascorbate, sodium citrate anhydrous, sodium citratedihydrate, sodium sulfide, sodium sulfite, sodium bisulfite, sodiumformaldehyde sulfoxylate, thioglycolic acid and sodium metabisulfite. 4.The solution according to claim 1, wherein a level of total impuritiesin the solution is less than 1.5% w/w as measured by HPLC, when saidsolution is stored at 40° C./75% RH for 6 months.
 5. The solutionaccording to claim 1, wherein a level of Impurity B in the solution isless than 0.5% w/w as measured by HPLC, when said solution is stored at40° C./75% RH for 6 months.
 6. The solution according to claim 1,wherein the concentration of the anti-oxidant ranges from about 0.01% toabout 50% w/w of the solution.
 7. The solution according to claim 1,wherein the anti-oxidant is present at a concentration of about 0.05%w/w of the solution.
 8. The solution according to claim 1, wherein theantioxidant is tartaric acid.
 9. The solution according to claim 8,wherein the tartaric acid is present in the concentration of about 0.05%w/w of the solution.
 10. The solution according to claim 8, wherein thetartaric acid is present in an amount of 0.5 mg/mL.
 11. The solutionaccording to claim 1, wherein the antioxidant is present, and wherein aweight ratio of the anti-oxidant to tofacitinib is from about 0.1:1 toabout 1:10.
 12. The solution according to claim 1, wherein 1 mg oftofacitinib is provided as 1.62 mg of tofacitinib citrate.
 13. A stablesolution of tofacitinib comprising: tofacitinib at a concentration ofabout 1 mg/mL, optionally one or more antioxidants; and apharmaceutically acceptable liquid vehicle selected from the groupconsisting of water, purified water, ethanol or a combination thereof;wherein a pH of the solution ranges from about 3.7 to 4.5; wherein thesolution is free from precipitation when said solution is stored at 25°C./60% RH for at least 6 months; and wherein said solution is apalatable oral solution.
 14. The solution according to claim 13, whereinthe said solution further comprises one or more additionalpharmaceutically acceptable excipients selected from the groupconsisting of stabilizers, solubilizers, pH adjusting agents, bufferingagents, thickening agents, chelating agents, preservatives, flavoringagents, sweetening agents, coloring agents and mixtures thereof.
 15. Thesolution according to claim 13, wherein the antioxidant is selected fromthe group consisting of sodium bisulfate, ascorbic acid, ascorbylpalmitate, citric acid, tartaric acid, glycine, L-cysteinehydrochloride, L-methionine, butylated hydroxy anisole (BHA), butylatedhydroxytoluene (BHT), hydro phosphorous acid, monothioglycerol, propylgallate, sodium ascorbate, sodium citrate anhydrous, sodium citratedihydrate, sodium sulfide, sodium sulfite, sodium bisulfite, sodiumformaldehyde sulfoxylate, thioglycolic acid and sodium metabisulfite.16. The solution according to claim 13, wherein a level of totalimpurities in the solution is less than 1.5% w/w as measured by HPLC,when said solution is stored at 40° C./75% RH for 6 months.
 17. Thesolution according to claim 13, wherein a level of Impurity B in thesolution is less than 0.5% w/w as measured by HPLC, when said solutionis stored at 40° C./75% RH for 6 months.
 18. The solution according toclaim 13, wherein the concentration of the antioxidant ranges from about0.01% to about 50% w/w of the solution.
 19. The solution according toclaim 13, wherein the antioxidant is present at a concentration of about0.05% w/w of the solution.
 20. The solution according to claim 13,wherein the antioxidant is tartaric acid.
 21. The solution according toclaim 20, wherein the tartaric acid is present in the concentration ofabout 0.05% w/w of the solution.
 22. The solution according to claim 20,wherein the tartaric acid is present in an amount of 0.5 mg/mL.
 23. Thesolution according to claim 13, wherein the antioxidant is present, andwherein a weight ratio of the antioxidant to tofacitinib is from about0.1:1 to about 1:10.
 24. The solution according to claim 13, wherein 1mg of tofacitinib is provided as 1.62 mg of tofacitinib citrate.